Phosphorous organic compounds and their use

ABSTRACT

Use of phosphorous organic compounds of general formula (I)  
                 
 
     wherein B represents either an ether group of the formula (II)  
                 
 
     or a keto group of the formula (III)  
                 
 
     is a 5 or 6 membered cyclic compound,  
     and their use for preparing pharmaceutical compositions for the therapeutic and prophylactic treatment of infections in humans and animals due to viruses, bacteria, fungi, and parasites as well as their use as a fungicide, bactericide and herbicide in plants.

[0001] The invention relates to phosphorous organic compounds and theirsalts, esters, and amides as well as their use for preparingpharmaceutical compositions for therapeutic and prophylactic treatmentof infections in humans and animals caused by viruses, bacteria, fungi,and parasites and the use thereof as a fungicide, bactericide, andherbicide in plants. According to the invention the phosphorous organiccompounds comprise phosphinoyl derivatives, phosphinic acid derivativesand phosphonic acid derivatives.

[0002] There is a serious need for the provision of preparations toenhance the treatment of humans and animals and the protection ofplants, which preparations not only possess a strong efficacy but incontrast to other pharmaceutical compositions and plant protectiveagents, contain reduced side effects and lower environmental impact andtherefore represent a lower risk to health for humans.

[0003] The object of the present invention is therefore to provide asubstance which can be universally used in infections by viruses,bacteria, fungi, and parasites in humans and animals and as a fungicide,bactericide, and herbicide in plants and fulfils the conditions givenabove.

[0004] This object is achieved in a completely surprising manner by thegroup of substances defined in claim 1. This group of substancesdemonstrates an anti-infectious effect against viruses, bacteria, fungi,unicellular and multicellular parasites as well as a fungicidal,bactericidal and herbicidal effect in plants.

[0005] The phosphorous organic compounds according to the inventioncorrespond to general formula (I):

[0006] in which R₁ and R₂ are the same or different and are selectedfrom the group, which consists of hydrogen, substituted andunsubstituted alkyl, substituted and unsubstituted hydroxyalkyl,substituted and unsubstituted alkenyl, substituted and unsubstitutedalkinyl, substituted and unsubstituted aryl, substituted andunsubstituted acyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted aralkyl, substituted and unsubstitutedheterocyclic radicals, halogen, OX₁ and OX₂,

[0007] wherein X₁ and X₂ may be the same or different and are selectedfrom the group, which consists of hydrogen, substituted andunsubstituted alkyl, substituted and unsubstituted hydroxyalkyl,substituted and unsubstituted alkenyl, substituted and unsubstitutedalkinyl, substituted and unsubstituted aryl, substituted andunsubstituted acyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted aralkyl, substituted and unsubstitutedheterocyclic radicals,

[0008] B is selected from the group, which consists of ether group (II)

[0009] wherein A₁ and A₂, out of which A₂ also may be absent, are thesame or different and are selected from the group, which consists ofalkylene radicals, alkenylene radicals and hydroxyalkylene radicals,

[0010] keto group (III)

[0011] wherein A₃ and A₄, out of which one or both may be absent, arethe same or different, are selected from the group, which consists ofalkylene radicals, alkenylene radicals and hydroxyalkylene radicals,

[0012] and 5 and 6 membered cyclic, in particular heterocycliccompounds, which contain additionally to carbon at least one heteroatomas a ring member, wherein the heteroatom is selected from the group,which consists of oxygen and nitrogen,

[0013] wherein R₃ and R₄ are the same or different and are selected fromthe group, which consists of hydrogen, substituted and unsubstitutedalkyl having up to 26 carbon atoms, substituted and unsubstitutedhydroxyalkyl having up to 26 carbon atoms, substituted and unsubstitutedaryl, substituted and unsubstituted acyl, substituted and unsubstitutedaralkyl, substituted and unsubstituted alkenyl having up to 26 carbonatoms, substituted and unsubstituted alkinyl having up to 26 carbonatoms, substituted and unsubstituted cycloalkyl, substituted andunsubstituted heterocyclic radicals, halogen, OX₃ or OX₄,

[0014] wherein X₃ or X₄ may be the same or different and are selectedfrom the group, which consists of hydrogen, substituted andunsubstituted alkyl having up to 26 carbon atoms, substituted aridunsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted andunsubstituted aryl, substituted and unsubstituted aralkyl, substitutedand unsubstituted alkenyl having up to 26 carbon atoms, substituted andunsubstituted alkinyl having up to 26 carbon atoms, substituted andunsubstituted cycloalkyl, substituted and unsubstituted heterocyclicradicals, a silyl, a cation of an organic and inorganic base, inparticular a metal of the first, second, or third main group of theperiodic system, ammonium, substituted ammonium and ammonium compoundswhich derive from ethylene diamine or amino acids,

[0015] and their pharmaceutically acceptable salts, esters and amidesand salts of the esters.

[0016] Compounds which correspond to formula (IV) are particularlypreferred

[0017] R₂ is selected from the group, which consists of acetyl andformyl,

[0018] A₁ is selected from the group, which consists of methylene,ethylene, ethenylene, hydroxyethylene, 2-hydroxypropylene, and

[0019] R₃ is selected from the group, which consists of hydrogen,methyl, ethyl, hexadecyl, octadecyl and OX₃, and

[0020] X₃ and X₄ are selected from the group, which consists ofhydrogen, sodium, potassium, methyl, ethyl, hexadecyl, and octadecyland, as far as both are present, may be the same or different.

[0021] Preferably the chain -A₁—O—C(ZY)— consists of one oxygen atom andtwo or three carbon atoms (substituents not included), particularlypreferably two carbon atoms.

[0022] Out of the ether compounds those compounds are particularlypreferred which are selected from the group, which consists of((N-formyl-N-hydroxyamino)-methoxy)-methylphosphonic acid disodium salt,((N-acetyl-N-hydroxyamino)-methoxy)-methyl phosphonic acid disodiumsalt, (2-(N-formyl-N-hydroxyamino)-etheneoxy)methylphosphonic aciddisodium salt, (2-(N-acetyl-N-hydroxyamino)etheneoxy)-methyl-phosphonicacid disodium salt,(3-(N-formyl-N-hydroxyamino)-2-hydroxypropoxy)-methylphosphonic aciddisodium salt,(3-(N-acetyl-N-hydroxyamino)-2-hydroxypropoxy)-methylphosphonic aciddisodium salt.

[0023] Furthermore compounds are preferred, which correspond to formula(V)

[0024] R₂ is selected from the group, which consists of acetyl andformyl,

[0025] A₁ is selected from the group, which consists of methylene,ethylene, ethenylene, hydroxymethylen, hydroxyethylene and2-hydroxypropylene,

[0026] A₂ is absent or methylene,

[0027] R₃ is selected from the group, which consists of hydrogen,methyl, ethyl, hexadecyl, octadecyl and OX₃, and

[0028] X₃ and X₄ are selected from the group, which consists ofhydrogen, sodium, potassium, methyl, ethyl, hexadecyl and octadecyl and,as far as both are present, may be the same or different.

[0029] Preferably the chain -A₁—CO-A₂— consists of two to four carbonatoms (substituents not included), particularly preferably of threecarbon atoms.

[0030] Out of these compounds2-(N-formyl-N-hydroxyamino)-1-oxoethylphosphonic acid disodium salt,2-(N-acetyl-N-hydroxyamino)-1-oxoethylphosphonic acid disodium salt,3-(N-formyl-N-hydroxyamino)-1-oxopropylphosphonic acid disodium salt,3-(N-acetyl-N-hydroxyamino)-1-oxopropylphosphonic acid disodium salt,3-(N-formyl-N-hydroxyamino)-1-oxo-2-propenylphosphonic acid disodiumsalt, 3-(N-acetyl-N-hydroxyamino)-1-oxo-2-propenylphosphonic aciddisodium salt,4-(N-formyl-N-hydroxyamino)-1-oxo-3-hydroxybutylphosphonic acid disodiumsalt, 4-(N-acetyl-N-hydroxyamino)-1-oxo-3-hydroxybutylphosphonic aciddisodium salt, 3-(N-formyl-N-hydroxyamino)-2-oxopropylphosphonic aciddisodium salt, 3-(N-acetyl-N--hydroxyamino)-2-oxoproylphosphonic aciddisodium salt,4-(N-formyl-N-hydroxyamino)-3-oxo-2-hydroxy-2-methylbutylphosphonic aciddisodium salt,4-(N-acetyl-N-hydroxyamino)-3-oxo-2-hydroxy-2-methylpropylphosphonicacid disodium salt,4-(N-formyl-N-hydroxyamino)-3-oxo-2-hydroxy-2-(hydroxymethyl)-butyl-phosphonicacid disodium salt,4-(N-acetyl-N-hydroxyamino)-3-oxo-2-hydroxy-2-(hydroxymethyl)-propylphosphonicacid disodium salt prove to be particularly preferred.

[0031] In the cyclic compounds the amino group and the phosphorus atommay be bound to optional C atoms of the ring. However, compounds arepreferred, in which they are bound to two C atoms which are separatedonly by one further atom. In the heterocyclic compounds the two carbonatoms are preferably separated by one heteroatom.

[0032] The following compounds are particularly preferred:

[0033] Special features of the above definitions and suitable examplesthereof are given below.

[0034] “Acyl” is a substituent which originates from an acid such asfrom an organic carboxylic acid, carbonic acid, carbamic acid or thethioacid or imidic acid corresponding to the individually present acids,or from an organic sulfonic acid, wherein in each case these acidscomprise aliphatic, aromatic and/or heterocyclic groups in the moleculeas well as carbamoyl or carbamimidoyl.

[0035] Suitable examples of these acyl groups were given below:.

[0036] Acyl radicals originating from aliphatic acid are designated asaliphatic acyl groups and include:

[0037] Alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl etc.);

[0038] alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl etc.);

[0039] alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl etc.)

[0040] alkane sulfonyl (e.g. mesyl, ethane sulfonyl, propane sulfonyletc.);

[0041] alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyletc.);

[0042] alkylcarbamoyl (for example methylcarbamoyl etc.);

[0043] (N-alkyl)-thiocarbamoyl (e.g. (N-methyl)-thiocarbamoyl etc.);

[0044] alkylcarbamimidoyl (e.g. methylcarbamimidoyl etc.);

[0045] oxalo;

[0046] alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).

[0047] In the above examples of aliphatic acyl groups the aliphatichydrocarbon part, in particular the alkyl group and the alkane radicalmay optionally contain one or more suitable substituents, such as amino,halogen (e.g. fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino,carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl,acylamino (e.g. benzy-loxycarbonylamino etc.), acyloxy (e.g. acetoxy,benzoyloxy etc.) and the like. Preferred aliphatic acyl radicals withsuch substituents are for example alkanoyls substituted with amino,carboxy, amino, and carboxy, halogen, acylamino or the like.

[0048] Acyl radicals originating from an acid with substituted orunsubstituted aryl groups, wherein the aryl group may comprise phenyl,toluyl, xylyl, naphthyl and the like are designated as aromatic acylradicals. Suitable examples are given below:

[0049] Aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.);

[0050] Aralkanoyl (for example phenylacetyl etc.);

[0051] Aralkenoyl (for example cinnamoyl etc.);

[0052] Aryloxyalkanoyl (for example phenoxyacetyl etc.);

[0053] Arylthioalkanoyl (for example phenylthioacetyl etc.);

[0054] Arylaminoalkanoyl (for example N-phenylglycyl, etc.);

[0055] Arene sulfonyl (for example benzene sulfonyl, tosyl bzw. toluenesulfonyl, naphthalene sulfonyl etc.);

[0056] Aryloxycarbonyl (for example phenoxycarbonyl,naphthyl-oxycarbonyl etc.);

[0057] Aralkoxycarbonyl (for example benzyloxycarbonyl etc.);

[0058] Arylcarbamoyl (e.g. phenylcarbamoyl, naphthylcarbamoyl etc.);

[0059] Arylglyoxyloyl (for example phenylglyoxyloyl etc.).

[0060] In the present examples of aromatic acyl radicals the aromatichydrocarbon part (in particular the aryl radical) and/or the aliphatichydrocarbon part (in particular the alkane radical) may optionallycontain one or more suitable substituents, such as those which werealready mentioned as suitable substituents of the alkyl group and thealkane radical. In particular and as an example for preferred aromaticacyl radicals with particular substituents, aroyl substituted withhalogen and hydroxy or with halogen and acyloxy and acyloxy andaralkanoyl substituted with hydroxy, hydroxyimino,dihalogenalkanoyloxyimino are mentioned as well as

[0061] arylthiocarbamoyl (for example phenylthiocarbamoyl etc.);

[0062] arylcarbamimidoyl (for example phenylcarbamimidoyl etc.).

[0063] A heterocyclic acyl radical is understood to be an acyl radicalwhich originates from an acid with heterocyclic group. These include:

[0064] Heterocyclic carbonyl in which the heterocyclic radical is anaromatic or aliphatic 5 to 6 membered heterocycle and has at least oneheteroatom from the group nitrogen, oxygen and sulfur (for examplethiophenyl, furoyl, pyrrolcarbonyl, nicotinoyl etc.);

[0065] heterocyclic alkanoyl, in which the heterocyclic radical is 5 to6 membered and has at least one heteroatom from the group nitrogen,oxygen and sulfur (for example thiophenyl-acetyl, furylacetyl,imidazolylpropionyl, tetrazolylacetyl,2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl etc.) and the like.

[0066] In the above examples of heterocyclic acyl radicals theheterocycles and/or the aliphatic hydrocarbon part may optionallycontain one or more suitable substituents, such as the same as thosewhich were mentioned as suitable for alkyl and alkane groups.

[0067] “Alkyl” is a straight- or branched-chain alkyl radical having upto 9 carbon atoms, unless defined otherwise, such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and thelike.

[0068] “Hydroxyalkyl” is a straight- or branched-chain alkyl radicalhaving up to 9 carbon atoms, unless defined otherwise, which at leastcomprises one hydroxy group, preferably one or two hydroxy groups.

[0069] “Alkenyl” includes straight- or branched-chain alkenyl groupswith up to 9 carbon atoms, unless defined otherwise, for example vinyl,propenyl (for example 1-propenyl, 2-propenyl), 1-methylpropenyl,2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexenyl.

[0070] “Alkinyl” includes straight- or branched-chain alkinyl radicalshaving up to 9 carbon atoms, unless defined otherwise.

[0071] Cycloalkyl preferably represents an optionally substitutedC₃-C₇-cycloalkyl; possible substituents are e.g. alkyl, alkenyl,alkinyl, alkoxy (for example methoxy, ethoxy etc.), halogen (z.B.fluorine, chlorine, bromine etc.), nitro and the like.

[0072] Aryl is an aromatic hydrocarbon radical such as phenyl, naphthyletc., which may optionally contain one or more suitable substituentssuch as alkoxy (for example methoxy, ethoxy etc.), halogen (for examplefluorine, chlorine, bromine etc.), nitro and the like.

[0073] “Aralkyl” includes mono-, di-, triphenylalkyls such as benzyl,phenethyl, benzhydryl, trityl and the like, wherein the aromatic partmay optionally contain one or more suitable substituents such as alkoxy(for example methoxy, ethoxy etc.), halogen (for example fluorine,chlorine, bromine etc.), nitro and the like.

[0074] “Alkylene” includes straight- or branched-chain alkylene groups,which contain up to 9 carbon atoms and may be represented by the formula

—(C_(n)H_(2n))—

[0075] in which n is an integer from 1 to 9, such as methylene,ethylene, trimethylene, methylethylene, tetramethylene,1-methyltrimethylene, 2-ethylethylene, pentamethylene,2-methyltetramethylene, isopropylethylene, hexamethylene, and the like.Preferred alkylene radicals contain up to 4 carbon atoms and radicalswith 3 carbon atoms, such as for example trimethylene, are particularlypreferred.

[0076] “Alkenylene” includes straight- or branched-chain alkenylenegroups with up to 9 carbon atoms which may be reproduced by the formula:

—(C_(n)H_(2n-2))—

[0077] in which n is an integer from 2 to 9, for example vinylene,propenylene (for example 1-propenylene, 2-propenylene),1-methylpropenylene, 2-methylpropenylene, butenylene,2-ethylpropenylene, pentenylene, hexenylene and the like. The alkenyleneradical may particularly preferably contain up to 5 carbon atoms and inparticular 3 carbon atoms, for example 1-propenylene. The hydrogen atomsmay also be replaced by substituents, such as for example halogenradicals.

[0078] “Hydroxyalkylene” may include straight- or branched-chainalkylene radicals which contain up to 9 carbon atoms, wherein one ormore selected carbon atoms are substituted with a hydroxy group. Theseradicals may be represented by the formula:

—(C_(n)H_(22n-z))(OH)_(z)—

[0079] in which n is an integer from 1 to 9 and z is an integer, towhich z≦n applies. Suitable examples of such hydroxyalkylene groupsinclude hydroxymethylene, hydroxyethylene (for example 1-hydroxyethyleneand 2-hydroxyethylene), hydroxytrimethylene (for example1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene),hydroxytetramethylene (for example 2-hydroxytetramethylene),2-hydroxy-2-methyltrimethylene, hydroxypentamethylene (for example2-hydroxypentamethylene), hydroxyhexamethylene (for example2-hydroxyhexamethylene) and the like. A lower hydroxyalkylene with up to4 carbon atoms is particularly preferred and in particular one with 3carbon atoms for example 2-hydroxytrimethylen. The hydrogen atoms mayalso be replaced by substituents, such as for example halogen radicals.

[0080] The 5 and 6 membered cyclic compounds, which may be representedby B, may be aromatic or aliphatic and substituted, for example by alkylgroups having up to 7 carbon atoms and hydroxy groups.

[0081] The 5 and 6 membered heterocyclic compounds, which may berepresented by B and contain additionally to carbon at least oneheteroatom as a ring member, may be saturated or unsaturated. Examplesare azixane, diazixane, azixine, diazixine, azolane, diazolane, azol,diazol, oxolane, dioxolene, oxol, dioxol, oxixane, dioxixane, oxixineand dioxixine. They-may be aliphatic or aromatic and may be substitutedfor example by alkyl groups having up to 7 carbon atoms and hydroxygroups.

[0082] Preferably, the radicals X₃ and X₄ may be selected such, thatesters form on the phosphono group or the phosphino group. Suitableexamples of esters of the compounds according to the formulae (I), (IV)to (IX) are suitable mono and diesters, and preferred examples of suchesters include alkylester (for example methylester, ethylester,propylester, isopropylester, butylester, isobutylester, hexylesteretc.);

[0083] aralkyl ester (benzyl ester, phenethyl ester, benzohydryl ester,trityl ester etc.);

[0084] aryl ester (for example phenyl ester, toluyl ester, naphthylester etc.); aroylalkyl ester (for example phenacyl ester etc.); andsilylester (for example of trialkylhalogensilyl, dialkyldihalogensilyl,alkyltrihalogensilyl, dialkylarylhalogensilyl, trialkoxyhalogensilyl,dialkylaralkylhalogensilyl, dialkoxydihalogensilyl,trialkoxyhalogensilyl etc.) and the like.

[0085] With the above ester the alkane and/or arene part may optionallycontain at least one suitable substituent such as halogen, alkoxy,hydroxy, nitro or the like.

[0086] X₃ and X₄ are preferably a metal of the first, second, or thirdmain group of the periodic system, ammonium, substituted ammonium, orammonium compounds, which derive from ethylene diamine or amino acids.In other words the salt compounds of the phosphorous organic compoundswith organic or inorganic bases (for example sodium salt, potassiumsalt, calcium salt, aluminum salt, ammonium salt, magnesium salt,triethylamine salt, ethanolamine salt, dicyclohexylamine salt,ethylenediamine salt, N,N′-dibenzylethylene diamine salt etc.) as wellas salts with amino acids (for example arginine salt, aspartic acidsalt, glutamic acid salt etc.) and the like are formed.

[0087] The compounds according to the invention in accordance with theformulae (I) to (IX) may be present on their protonized form as anammonium salt of organic or inorganic acids, such as hydrochloric acid,hydrobromic acid, sulfur acid, nitric acid, methanesulfonic acid,p-toluene sulfonic acid, acetic acid, lactic acid, maleic acid, fumaricacid, oxalic acid, tartaric acid, benzoic acid, etc.

[0088] The compounds according to the invention in accordance with theformulae (I), (IV) to (IX) permit for example the emergence of spatialisomers for groups containing double bonds or chiral groups R₁, R₂, R₃,R₄, X₁, X₂, X₃, X₄, A₁, A₂, A₃, A₄ and the heterocycles. The use of thecompounds according to the invention includes all spatial isomers bothas pure substances and in form of their mixtures.

[0089] The phosphorous organic compounds are in particular suited forthe therapeutic and prophylactic treatment of infections in humans andanimals caused by viruses, bacteria, unicellular and multicellularparasites and fungi.

[0090] The compounds are effective against unicellular parasites(protozoa), in particular against pathogens of malaria and the sleepingsickness as well as the Chagas' disease, the toxoplasmosis, amoebicdysentery, leishmaniasis, trichomoniasis, sarcocystosis,acanthamebiasis, naegleriasis, coccidiosis, giardiasis and lambliosis.

[0091] Therefore, they are particularly suitable as malariaprophylactics and as prophylactics of sleeping sickness as well as theChagas' disease, toxoplasmosis, amoebic dysentery, leishmaniasis,trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiasis,sarcocystosis, acanthamebiasis, naegleriasis, coccidiosis, giardiasisand lambliosis.

[0092] The active agents according to the invention may in particular beused against the following bacteria:

[0093] Bacteria of the family Propionibacteriaceae, in particular thegenus Propionibacterium, in particular the species Propionibacteriumacnes;

[0094] bacteria of the family Actinomycetaceae, in particular the genusActinomyces;

[0095] bacteria of the genus Corynebacterium, in particular the speciesCorynebacterium diphteriae and Corynebacterium pseudotuberculosis;

[0096] bacteria of the family Mycobacteriaceae, the genus Mycobacterium,in particular the species Mycobacterium leprae, Mycobacteriumtuberculosis, Mycobacterium bovis and Mycobacterium avium;

[0097] bacteria of the family Chlamydiaceae, in particular the speciesChlamydia trachomatis and Chlamydia psittaci;

[0098] bacteria of the genus Listeria, in particular the speciesListeria monocytogenes;

[0099] bacteria of the species Erysipelthrix rhusiopathiae;

[0100] bacteria of the genus Clostridium;

[0101] bacteria of the genus Yersinia, the species Yersinia pestis,Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersiniaruckeri;

[0102] bacteria of the family Mycoplasmataceae, the genus Mycoplasma andUreaplasma, in particular the species Mycoplasma pneumoniae; bacteria ofthe genus Brucella;

[0103] bacteria of the genus Bordetella;

[0104] bacteria of the family Neiseriaceae, in particular the genusesNeisseria and Moraxella, in particular the species Neisseriameningitides, Neisseria gonorrhoeae and Moraxella bovis;

[0105] bacteria of the family Vibrionaceae, in particular the genusesVibrio, Aeromonas, Plesiomonas and Photobacterium, in particular thespecies Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas;bacteria of the genus Campylobacter, in particular the speciesCampylobacter jejuni, Campylobacter coli and Campylobacter fetus;bacteria of the genus Helicobacter, in particular the speciesHelicobacter pylori;

[0106] bacteria of the families Spirochaetaceae and the Leptospiraceae,in particular the genus Treponema, Borrelia and Leptospira, inparticular Borrelia burgdorferi;

[0107] bacteria of the genus Actinobacillus;

[0108] bacteria of the family Legionellaceae, the genus Legionella;

[0109] bacteria of the family Rickettsiaceae and family Bartonellaceae;bacteria of the genus Nocardia and Rhodococcus; bacteria of the genusDermatophilus;

[0110] bacteria of the family Pseudomonadaceae, in particular thegenuses Pseudomonas and Xanthomonas;

[0111] bacteria of the family Enterobacteriaceae, in particular thegenuses Escherichia, Klebsiella, Proteus, Providencia, Salmonella,Serratia and Shigella; bacteria of the family Pasteurellaceae, inparticular the genus Haemophilus;

[0112] bacteria of the family Micrococcaceae, in particular the genusMicrococcus and Staphylococcus; bacteria of the family Streptococcaceae,in particular the genus Streptococcus and Enterococcus and bacteria ofthe family Bacillaceae, in particular the genus bacillus andclostridium.

[0113] Therefore the phosphorous organic compounds are suitable fortreatment of diphtheria, acne vulgaris, listeriosis, erysipelas inanimals, gas gangrene in humans and in animals, diseases in humans andanimals caused by clostridium septicum, tuberculosis in humans andanimals, leprosy, and further mycobacteriosis in humans and animals,paratuberculosis in animals, pestis, mesenterial lymphadenitis andpseudotuberkulosis in humans and animals, cholera, legionnaires disease,borrelioses in humans and animals, leptospiroses in humans and animals,syphilis, campylobacter enteritides in humans and animals, moraxellakeratoconjunctivitis and serositis in animals, brucelloses in animalsand in humans, anthrax in humans and animals, actinomycosis in humansand animals, streptotrichosis, psittakosis/ornithosis in animals,Q-fever, ehrlichiosis.

[0114] Further the use is advantageous in helicobacter eradicationtherapy of ulcera of the gastrointestinal tract.

[0115] Further combinations with an additional antibiotic may also beused for treatment of the above mentioned diseases. As combinedpreparations with other antiinfective agents in particular isoniazide,rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide anddapsone are suitable for the treatment of tuberculosis

[0116] The active agents according to the present invention mayfurthermore be used in particular in infections with following viruses:

[0117] Parvoviridae: parvo viruses, dependo viruses, Denso viruses;

[0118] Adenoviridae: adeno viruses, mastadeno viruses, aviadeno viruses;Papovaviridae: papova viruses, in particular papilloma viruses (socalled wart viruses), Polyoma viruses, in particular JC virus, BK virus,and miopapova viruses; herpes viruses: all herpes viruses, in particularherpes simplex viruses, the varizella-zoster viruses, human cytomegalovirus, Epstein-Barr viruses, all human herpes viruses, human herpesvirus 6, human herpes virus 7, human herpes virus 8; Poxyiridae: poxviruses, orthopox, parapox, molluscum contagiosum virus, avipox viruses,capripox viruses, leporipox viruses; all primary hepatotropic viruses,Hepatitis viruses: hepatitis A viruses, hepatitis B viruses, hepatitis Cviruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses,hepatitis G viruses;

[0119] Hepadna viruses: all hepatitis viruses, hepatitis B virus,hepatitis D viruses; Picornaviridae: picorna viruses, all enteroviruses, all polio viruses, all coxsackie viruses, all echo viruses, allrhino viruses, hepatitis A virus, aphtho viruses; Calciviridae:hepatitis E viruses; Reoviridae: reo viruses, orbi viruses, rotaviruses; Togaviridae: toga viruses, alpha viruses, rubi viruses, pestiviruses, rubella virus;

[0120] Flaviviridae: flavi viruses, ESME virus, hepatitis-C-Virus;

[0121] Orthomyxoviridae: all influenza viruses; Paramyxoviridae:paramyxo viruses, morbilli virus, pneumo virus, measles virus, mumpsvirus; Rhabdoviridae: rhabdo viruses, rabies virus, lyssa virus, visculastomatitis virus; Corona viridae: corona viruses; Bunyaviridae: bunyaviruses, nairo virus, phlebo virus, uuku virus, hanta virus;Arenaviridae: arena viruses, lymphocytic choriomeningitis-virus;Retroviridae: retro viruses, all HTL viruses, human T-cell leukaemiavirus, oncorna viruses, spuma viruses, lenti viruses, all HI-viruses;Filoviridae: Marburg and Ebola virus; Slow-virus-infections, prions;Onco viruses, leukemia viruses.

[0122] The phosphororganic compounds according to the invention aretherefore suitable for fighting the following viral infections:

[0123] Eradication of papilloma viruses to prevent tumors, in particulartumors in the sexual organs caused by papilloma viruses in humans,eradication of JC viruses and BK viruses, eradication of herpes viruses,eradication of human herpes viruses 8 for the treatment of Kaposi'ssarcoma, eradication of cytomegalo viruses before transplants,eradication of Eppstein-Barr viruses before transplants and to preventtumors associated with Eppstein-Barr viruses, eradication of hepatitisviruses for the treatment of chronic liver diseases and for theprevention of tumors of the liver and cirrhosis of the liver,eradication of coxsackie viruses patients with cardiomyopathy,eradication of coxsackie viruses in diabetes mellitus patients,eradication of immune system debilitating viruses in humans and animals,treatment of secondary infections in AIDS-patients, treatment ofinflammations of viral origin of the respiratory tract (larynxpapillomas, hyberplasias, rhinitis, pharyngitis, bronchitis,pneumonias), of the sensory organs (Keratoconjunctivitis), of thenervous system (poliomyelitis, meningoenzephalitis, encephalitis,subacute sklerosing panencephalitis SSPE, progressive multifocalleukoencephalopathie, lymphocytic choriomeningitis), of thegastrointestinal tract (stomatitis, gingivostomatitis, oesophagitis,gastritis, gastroenteritis, diarrhoea-causing diseases), the liver andthe gall bladder system (hepatitis, cholangitis, hepatocellularcarcinoma), of the lymphatic tissue (mononucleosis, lymphadenitis), ofthe haematopoetic system, of the sexual organs (mumpsorchitis), of theskin (warts, dermatitis, herpes labialis, heat rush, herpes zoster,shingles), of the mucous membranes (papillomas, conjunctiva papillomas,hyperplasias, dysplasias), of the heart/blood vessel system (arteriitis,myocarditis, endocarditis, pericarditis), the kidney/urinary tractsystems, of the sexual organs (anogenital lesions, warts, genital warts,acute condylomas, displasias, papillomas, cervix dysplasias, condylomataacuminata, epidermodysplasia verruci formis), of the organs of motion(myositis, myalgien), treatment of foot and mouth diseases incloven-hoofed animals, of Colorado tick fever, of Dengue-syndrome, ofhaemorrhagic fever, of early summer meningoencephalitis (FSME) and ofyellow fever.

[0124] The described compounds, i.e. the phosphorous organic compoundsaccording to formulae (I), (IV) to (IX) and esters and amides thereofformed on the phosphono group or the phosphino group as well as saltsthereof show a strong cytotoxic efficacy against bacteria, fungi,viruses, unicellular and multicellular parasites. Therefore thecompounds according to the invention are usable in the treatment ofinfectious diseases caused by viruses, bacteria, parasites, and fungi inhumans and animals. The compounds also are suited for use inprophylactics of diseases due to viruses, bacteria, parasites, andfungi, in particular in prophylactics of malaria and in prophylactics ofthe sleeping sickness.

[0125] The phosphorous organic compounds according to the inventionwhich generally include pharmaceutically acceptable salts, amides,esters, a salt of such an esters or else compounds which uponapplication provide the compounds use according to the inventionmetabolic products or decomposition products, also called “prodrugs” mayall be prepared for administration like known anti-infectious agents inany suitable manner (mixed with non-toxic pharmaceutically acceptablecarriers).

[0126] Pharmaceutically acceptable salts of the aminohydrophosphonicacid derivative include salts, which form the compounds of formulae (I),(IV) to (IX) in their protonised form as an ammonium salt of inorganicor organic acids, such as hydrochloric acid, sulfur acid, citric acid,maleic acid, fumaric acid, tartaric acid, p-toluene sulfonic acid.

[0127] Salts which are formed by suitable selection of X₃ and X₄ areespecially suited, such as sodium salt, potassium salt, calcium salt,ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylaminesalt and salts of amino acid such as arginine salt, aspartic acid salt,glutamic acid salt.

[0128] The activity of substances is determined in a test system. Thissystem is based on the measuring of the inhibition of growth ofbacteria,-parasites, viruses, fungi or plants in vitro. To this end,test procedures are used, some of which are known to the person skilledin the art.

[0129] To determine the anti-malaria activity, for example, theinhibition of the growth of malaria parasites in blood cultures isdetermined.

[0130] The determining of the anti-bacterial activity, for example isbased on the measurement of the inhibition of the growth of bacteria onculture media and in liquid cultures.

[0131] The determining of the anti-viral activity is based on theinhibition of the formation of viral elements in cell cultures.

[0132] The determining of fungicidal activity is based on the inhibitionof the growth of fungi on culture media and in liquid cultures.

[0133] Some of the microorganism which should be investigated can onlybe investigated in animal models. In this case we will use thecorresponding model.

[0134] Substances which demonstrate an efficacy in the in vitromeasuring system will be further investigated in in vivo models.

[0135] The anti-parasitic, antiviral or fungicide activity will befurther evaluated in the appropriate animal model.

[0136] The screening of herbicidal activity is determined by algaesystems and measurement of the isoprene emission of plants at standardconditions.

[0137] The pharmaceutically effective preparations may be prepared inthe form of pharmaceutical preparations in dispensing units. This meansthat the preparations can be present in the form of individual parts,for example tablets, dragees, capsules, pills, suppositories andampoules, the active ingredient content of which corresponds to afraction or a multiple of a single dose. The dispensing units can, forexample, contain 1, 2, or 4 single doses or ½, ⅓ or ¼ of a single dose.A single dose preferably contains the quantity of active ingredientwhich is administered during one application and which usuallycorresponds to a whole, a half or third of a quarter of a daily dose.

[0138] Non-toxic, inert pharmaceutically suitable carriers areunderstood to mean solid, semi-solid or liquid di-uents, fillers andformulation auxiliary agents of all kinds.

[0139] Tablets, dragees, capsules, pills, granules, suppositories,solutions, suspensions and emulsions, pastes, ointments, gels, creams,lotions, powders and sprays are mentioned as preferred pharmaceuticalpreparations. Tablets, dragees, capsules, pills and granules may containin addition to the conventional excipients the active ingredient, suchas (a) fillers and diluents, for example starches, lactose, cane sucar,glucose, mannitol and silicic acid, (b) binders, for examplecarboxymethylcellulosis, alginate, gelatine, polyvinylpyrrolidone, (c)moisture-retaining agents, for example glycerol, (d) dispersing agents,for example agar-agar, calcium carbonate and sodium carbonate, (e)solution retarders, for example paraffin and (f) resorptionaccelerators, for example quaternary ammonium compounds, (g) wettingagents, for example cetyl alcohol, glycerol monostearate, (h) adsorptionagents, e.g. kaolin and betonite and (i) lubricants, for example talcum,calcium and magnesium stearate and solid polyethylene glycol or mixturesof the substances listed under (a) to (i).

[0140] The tablets, dragees, capsules, pills and granules may beprovided with the conventional coatings and casings optionallycomprising opaquing agents and may also be put together so that theyrelease the active ingredient or active ingredients only or preferablyin a specific part of the intestinal optionally with sustain release,wherein polymer substances and waxes for example may be used asembedding compounds.

[0141] The active ingredient or the active ingredients may optionallyalso be present in microencapsulated form with one or more of the abovementioned excipients.

[0142] In addition to the active ingredient or the active ingredientssuppositories may also contain the conventional water soluble or waterinsoluble excipients, for example polyethylene glycols, fats, forexample cacoa fat and higher esters (for example C₁₄— alcohol withC₁₆-fatty acid) or mixtures of these substances.

[0143] In addition to the active ingredients ointments, pastes, creamsand gels may contain the conventional excipients, for example animal andvegetable fats, waxes, paraffins, starch, tragacanth, cellulosederivative, polyethylene glycols, silicones, bentonites, silicic acid,talcum and zinc oxide or mixtures of these substances.

[0144] In addition to the active ingredients powders and sprays maycontain the conventional excipients, for example lactose, talcum,silicic acid, aluminium hydroxide, calcium silicate and polyamide powderor mixtures of these substances. Sprays may additionally contain theconventional blowing agents, for example chlorofluorohydrocarbons.

[0145] In addition to the active ingredients solutions and emulsions maycontain the conventional excipients such as solvents, solubilisers andemulgators, for example water, ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, inparticular cotton seed oil, peanut oil, corn oil, olive oil, castor oiland sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol,polyethyleneglycols and fatty acid esters of sorbitan or mixtures ofthese substances.

[0146] The solutions and emulsions may also be present in sterile andblood isotonic form for parenteral application.

[0147] In addition to the active ingredients suspensions may containconventional excipients such as liquid diluents, for example water,ethyl alcohol, propylene glycol, suspending agents, for exampleethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitanesters, microcrystalline cellulose, aluminium metahydroxide, bentonite,agar-agar and tragacanth or mixtures of these substances.

[0148] The above-mentioned formulations can also contain dyes,preservatives and odour and flavour improving additives, for examplepeppermint oil and eucalyptus oil and sweeteners, for examplesaccharine.

[0149] The active agents of formulae (I), (IV) to (IX) should be presentin the above listed pharmaceutical preparations preferably in aconcentration of approximately 0.1 to 99.5% by weight, preferably ofapproximately 0.5 to 95% by weight of the total mixture.

[0150] In addition to the compounds of formulae (I), (IV) to (IX) thepharmaceutical preparations may also contain further pharmaceuticalagents.

[0151] The compounds may be used with hereto described substances withantimicrobial, antiviral, antifungal and antiparasitic properties.Compounds which have already found application in treatment or are stillbeing used belong in particular to this group. Substances which arelisted in the Red List or Simon/Stille, Antibiotika-Therapie in Klinikund Praxis, 9.Auflage 1998 Schattauer Verlag, or underhttp:/www.customs. treas.gov/imp-exp/rulings/harmoniz/hrm129.html on theInternet are particularly suitable for this purpose. In particularderivatives with penicillins, benzyl penicillin (Penicillin G), phenoxypenicillins, isoxazolyl penicillins, amino penicillins, ampicillin,amoxicillin, bacampicillin, carboxy penicillin, ticarcillin, temocillin,acyalamino penicillins, azlocillin, mezlocillin, piperacillin,apalcillin, mecillinam, cephalosporins, cefazolin group, cefuroximegroup, cefoxitin group, cefoxitin, cefotetan, cefinetazole, latamoxef,flomoxef, cefotaxime group, cefozidime, ceftazidime group, ceftazidime,cefpirom, cefepim, remaining cephalosporins, cefsulodine, cefoperazone,oralcephalosporins of the cefalexin group, loracarbef, cefprozil, neworalcephalosporins with expanded spectrum, cefixime, cefpodoximeproxetil, cefuroxime axetil, cefetamet, cefotiam hexetil, cefdinir,ceftibutene, other β-lactam antibiotics, carbapenem,imipenem/cilastatin, meropenem, biapenem, aztreonam, β-lactamaseinhibitors, calvulanic acid/amoxicillin, Clavulanic acid/ticarcillin,sulbactam/ampicillin, tazobactam/piperacillin, tetracyclines,oxytetracycline, rolitetracyclines, doxycycline, minocycline,chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin,amikacin, spectinomycin, macrolides, erythromycin, clarithromycin,roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin,lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics,vancomycin, tecoplanin, pristinamycin derivatives, fosfomycin,antimicrobial folic acid antagonists, sulphonamides, co-trimoxazole,trimethoprim, other diaminopyrimidine sulfonamide combinations,nitrofurans, nitrofurantoin, nitrofurazone, Gyrase inhibitors(quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin,enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118,nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin,rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin,prothionamide, terizidon, dapsone, clofazimine, topical antibiotics,bacitracin, tyrothricin, polymyxins, neomycin, kanamycin, paromomycin,mupirocin, antiviral agents, acyclovir, ganciclovir, azidothymidine,didanosin, zalcitabin, thiacytidine, stavudin, ribavirin, idoxuridine,trifluridine, foscarnet, amantadine, interferons, tibol derivatives,proteinase inhibitors, antifungal agents, polyenes, amphothericin B,nystatin, natamycin, azoles, azoles for septic treatment, miconazole,ketoconazole, itraconazole, fluconazole, UK-109.496, azoles for topicalapplication, clotrimazole, econazole, isoconazole, oxiconazole,bifonazole, flucytosine, griseofulvin, ciclopiroxolamine, tolnaftate,naftifine, terbinafine, amorolfine, antraquinones, betulinic acid,semianthrachinones, xanthones, naphtoquinones, aryaminoalcohols,quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine,acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone,sulphonamides, sulfadoxine, sulfalenes, trimethoprim, proguanil,chlorproguanil, diaminopyrimidines, pyrimethamine, primaquine,aminoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin,norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin,10b arte mether, arte ether, arte sunate, atovaquon, suramin,melarsoprol, nifurtimox, stibogluconate-sodium, pentamidine,amphotericine B, metronidazole, clioquinole, mebendazole, niclosamide,praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin,bithionol, oxamniquine, metrifonate, piperazine, embonate can [be used].

[0152] Furthermore the phosphorous organic compounds may be present inthe pharmaceutical preparations in combination with sulfonamide,sulfadoxin, artemisinin, atovaquon, chinin, chloroquine,hydroxychloroquin, mefloquin, halofantrin, pyrimethamine, armesin,tetracycline, doxycyclin, proguanil, metronidazol, praziquantil,niclosamide, mebendazol, pyrantel, tiabendazole, diethylcarbazin,piperazin, pyrivinum, metrifonate, oxamniquin, bithionol or suramin orseveral of these substances.

[0153] The above listed pharmaceutical preparations are produced in theconventional manner by known methods, for example by mixing the activeingredient or active ingredients with the excipient or excipients.

[0154] The above-mentioned preparations can be used in humans andanimals either orally, rectally, parentally, (intravenously,intramuscularly, subcutaneously), intracisternally, intravaginally,intraperitoneally, topically (powder, ointment, drops) and for thetreatment of infections in cavities, orifices. Suitable preparations areinjection solutions, solutions and suspensions for oral treatment, gels,infusions, emulsions, ointments or drops. Ophthalmological anddermatogical formulations, silver and other salts, eardrops, eyeointments, powders or solutions can be used for topical treatment. Withanimals the absorption can occur via the food or drinking water insuitable formulations. Furthermore gels, powders, tablets, sustainrelease tablets, premixes, concentrates, granules, pellets, tablets,boli, capsules, aerosoles, sprays, inhalers can be used with humans andanimals. The compounds according to the invention can furthermore beincorporated into other carrier materials such as, for example, plasticmaterials (plastic-chains for topical treatment), collagen or bonecement.

[0155] In general it has proved advantageous both in human andveterinary medicine to administer the active ingredient or ingredientsof formulae (I), (IV) to (IX) in total quantities of approximately 0.05to approximately 600, preferably 0.5 to 200 mg/kg body weight per 24hours, optionally in the form of several individual doses in order toachieve the desired results. An individual dose contains the activeingredient or ingredients preferably in quantities of approximately 1 toapproximately 200, in particular 1 to 60 mg/kg body weight. It may,however, be necessary to deviate from the above-mentioned dosages andthis is dependent on the nature and the body weight of the patient to betreated, the nature and the severity of the disease, the nature and themethod and the application of the pharmaceutical compositions as well asthe time scale or interval within the administration takes place.

[0156] Thus in some cases it may be sufficient to get by with less thanthe above mentioned quantity of active ingredient, whilst in other casesthe above-stated quantity of active ingredient must be exceeded. Theperson skilled in the art may determine the optimum dosage and method ofapplication of the active ingredient in each case by virtue of hisexpert experience.

[0157] The compounds according to the invention may be administered inanimals in the conventional concentrations and preparations togetherwith the feed or feed preparations or the drinking water.

[0158] Furthermore compounds according, to the invention may beexcellently used as bactericides, fungicides and herbicides in plants.

[0159] Principally a person skilled in the art knows which way ofsynthesis for preparing the substances according to the invention he hasto choose. In the following some ways of synthesis for compounds of theinvention are given by example.

[0160] Possible Ways of Synthesis of Compounds Looking Like:

$\begin{matrix}{{{with}\quad R} = \quad {H\quad {or}\quad {Na}^{+}}} & \quad \\{{{and}\quad X} = {{{—CH}_{2}{—Y}} = {{witout}\quad {Y\left( {5\quad {memberd}\quad {ri}\quad {ng}} \right)}}}} & {{Example}\quad 1} \\{\quad {= {{—CH}_{2}—\quad \left( {6\quad {membered}\quad {ri}\quad {ng}} \right)}}} & {{Example}\quad 2} \\{\quad {{—O—}\quad = {{without}\quad {Y\left( {5\quad {memberd}\quad {ri}\quad {ng}} \right)}}}} & {{Example}\quad 3} \\{\quad {= {{—CH}_{2}—\quad \left( {6\quad {membered}\quad {ri}\quad {ng}} \right)}}} & {{Example}\quad 4} \\{\quad {{—NH—}\quad = {{without}\quad {Y\left( {5\quad {memberd}\quad {ri}\quad {ng}} \right)}}}\quad} & {{Example}\quad 5} \\{\quad {= {{—CH}_{2}—\quad \left( {6\quad {membered}\quad {ri}\quad {ng}} \right)}}} & {{Example}\quad 6}\end{matrix}$

EXAMPLE 1

[0161] 3-Oxo-cyclopentylphosphonic Acid Diethylester 1(a)

[0162] 0.52 mmol trimethylsilyltriflate are added dropwise to 11.4 mmoldiethylphosphite and 12.4 mmol N,O-bis-(trimethylsilyl) acetamid in 5 mldichlormethane at 0° C. After 30 minutes of stirring 0.52 mmol2-cyclopenten-1-one are added dropwise thereto at the same temperatureand stirring is continued for 1 h. The enolsilane intermediate productis hydrolized by 3 ml 1 n HCl and 3 hours of stirring. The organic phaseis separated, dried over magnesiumsulfate and concentrated. The rawproduct may be chromatographed on SiO₂ and, after concentrating thedesired fractions, results to 3-(phosphonic aciddiethylester)-cyclopentan-1-one (a) with boiling pointo_(0.25) Torr=104°C. in a good yield.

[0163] (Compare I. Mori, Y. Kimura, T. Nakano, S. Matsunaga, G. Iwasaki,A. Ogawa, K. Hayakawa, Tetrahedron Letters 1997, 38, 3543-46, R. G.Harvey, Tetranedron 1966, 22, 2561-73 and E. Öhler, E. Zbiral, LiebigsAnn. Chem. 1991, 229-36)

[0164] 3-(Phosphonic Acid Diethylester)-cyclopentanone Oxime 1(b)

[0165] 1.41 mmol N,O-bis-(trimethylsilyl)-hydroxyamine—dissolved inTHF—are added to a suspension of 150 mg 35% potassiumhydrid in mineraloil—also dissolved in THF—and cooled to −78° C. The suspension isstirred for 30 min at 0° C. At −78° C. 1.34 mmol 3-oxopentylphosphonicacid diethylester (a)—in THF—are added dropwise thereto. The reactionmixture is stirred for 90 min at room temperature, then added to 40 mlice cooled watery 10% ammoniumchloride solution and extracted threetimes with 30 ml methylenechiloride respectively. The combined organicphases are dried over MgSO₄ and the solvent is removed under reducedpressure. The oxime 1 may be furthermore converted without furtherpurification.

[0166] (Compare R. V. Hoffman, G. A. Buntain, Synthesis 1987, 9, 831-33or an alternative preparation: T. Kawada, T. Tsushima, Heterocycles,1989, 28, 573-578)

[0167] 3-N-(Hydroxyamine)cyclopentylphosphonic Acid Diethylester 1(c)

[0168] Sodium cyanohydrideborate (NaBH₃CN) is used without furtherpurification. To 4 mmol oxime 1(b) dissolved in little methanol 2 dropsof bromocresol green is supplied and 6 n KOH is added dropwise theretountil a change of colour from yellow to green is observed. 3 mmolNaBH₃CN are added, stirred for 3 h at room temperature and quencheddropwise with methanol/HCl until a change of colour from green to yellowis observed. The reaction mixture is added to 10 ml of water andadjusted to pH>10 with 6 n KOH. After the watery phase is saturated withNaCl the solution is extracted 5 times with 10 ml chloroformrespectively, dried over MgSO₄ and removed under reduced pressure. Theyellow to red coloured raw product may be chromatographed on SiO₂.

[0169] (Compare R. F. Borch, M. D. Bernstein, H. D. Durst, J Am Chem Soc1971, 93, 2897-904)

[0170] 3-N-(Hydroxyamine)-cyclopentylphosphonic Acid 1(d)

[0171] 130 ml concentrated HCl are added to 0.06 mol ester) with coolingwith ice and heated under vigorous stirring under reflux for 6 h. Aftercooling-off the yellow-brown coloured solution is concentrated underreduced pressure, taken up in approximately 30 ml of water and istreated with active carbon until a nearly colourless solution isproduced. This is concentrated again under reduced pressure, taken upwith approximately 30 ml of water and a pH of 4-5 is adjusted withNaHCO₃. The beige precipitate is filtered and can be washed withwater/ethanol. 0.037 mol product is formed corresponding to a yield of61%. Recrystallization is not necessary.

[0172] 3-(N-formyl-N-hydroxyamino)-cyclopentylphosphonic Acid MonoSodium Salt 1(e)

[0173] 2 ml formic acid are added dropwise to 4 ml acetic anhydride at0° C. within 5-10 min, are stirred for 10 min at the same temperatureand for 15 min at room temperature, and the solution is cooled again to0° C. 0.02 mol 3-N-(hydroxyamine) cyclopentylphosphonic acid (d) aredissolved in app. 6 ml formic acid during heating up to 40-50° C. andare added dropwise to the above solution at 0° C. and are stirred for 1h at ambient temperature. Then it is concentrated to an oil underreduced pressure, taken up in water and concentrated under reducedpressure. This method is carried out for three times. In watery solutiona pH of 4.5-5 is adjusted with 1 n NaOH. The resulting oil is extractedin isopropanol for several times whilst discarding the alcohol phase.The residue is taken up in methanol—until all is dissolved in theheat—and the product is precipitated by ethanol. After filtration of theraw product it may be recrystallised from methanol/ethanol once again.

EXAMPLE 2

[0174] 3-Oxo-cyclohexylphosphonic Acid Diethylester 2(a)

[0175] 0.52 mmol trimethylsilyltriflate is added dropwise to 11.4 mmoldiethylphosphite and 12.4 mmol N,O-bis-(trimethylsilyl) acetamide in 5ml dichlormethane at 0° C. After 30 minutes of stirring at the sametemperature 0.52 mmol 2-cyclohexen-1-one are added dropwise thereto andis stirred for 1 h. The enolsilane intermediate product is hydrolized by3 ml 1 n HCl during 3 hours of stirring. The organic phase is separated,dried over magnesiumsulfate and concentrated. The raw product can bechromatographed on SiO₂ and after concentration of the desired fractionsresults in 3-oxo-cyclohexylphosphonic acid diethylester 2(a) in a 95%yield.

[0176] (Compare I. Mori, Y. Kimura, T. Nakano, S. Matsunaga, G. Iwasaki,A. Ogawa, K. Hayakawa, Tetrahedron Letters 1997, 38, 3543-46)

[0177] 3-(Phosphonic Acid Diethylester)cyclohexanone Oxime 2(b) 2(b) maybe Synthesized by Analogy to 1(b).

[0178] 3-N-(hydroxyamine)-cyclohexylphosphonic Acid Diethylester 2(c)

[0179] Sodium cyanohydrideborate (NaBH₃CN) is used without furtherpurification. To 4 mmol oxime 2(b) dissolved in little methanol 2 dropsof bromocresole green are added and 6 n KOH is added dropwise theretountil a change of colour from yellow to green is observed. 3 mmolNaBH₃CN are added, stirred at room temperature for 3 h and quencheddropwise with methanol/HCl until a change of colour from green to yellowis observed. The reaction mixture is added to 10 ml water and a pH>10 isadjusted with 6 n KOH. After saturating the watery phase with NaCl thesolution is extracted for 5 times with 10 ml chloroforme respectively,dried over MgSO₄ and removed under reduced pressure. The yellow to redcoloured raw product may be chromatographed on SiO₂.

[0180] 3-N-(hydroxylamine)-cyclohexylphosphonic Acid 2(d)

[0181] 2(d) is obtained in analogy to the hydrolysis of 1(c) withconcentrated HCl in a yield of more than 50%.

[0182] 3-(N-formyl-N-hydroxyamino)cyclohexylphosphonic Acid MonosodiumSalt 2(e)

[0183] Preparation of 2(e) see 1(e).

EXAMPLE 3

[0184] 2,5-dichlorotetrahydrofurane 3(a)

[0185] At a temperature of −35° C. 142 g chlorine is condensed into 72 gabsolute THF in 80 ml tetrachloromethane, which is diluted withnitrogen. Then it is exposed to a UV-lamp under stirring for 8-9 h.After the transformation has been completed CCl₄ is removed underreduced pressure. The products are firstly condensed into a condenserunder high-vacuum which is cooled to −50° C., for being subsequentlyfractionated in water jet vacuum. 60 g 2,5-dichlorotetrahydrofuranehaving a boiling point_(12 Torr)=61-64° C. are achieved.

[0186] (Compare H. Gross, Chem. Ber 1962, 95, 83-90)

[0187] 5-chlorotetrahydrofuryl-2-(phosphonic acid di-tert-butylester)3(b)

[0188] 31 g (160 mmol) di-tert-butylphosphite—dissolved in 90 ml THF isadded dropwise to a suspension of 5.0 g 80% NaH (in mineral oil) in 60ml absolute THF at 0° C. After 30 minutes of stirring at 0° C. 135 mmol2,5-di-chlorotetrahydrofurane—dissolved in 120 ml absolute THF—is addeddropwise at the same temperature. The reaction solution is boiled underreflux for 20 h and then concentrated under reduced pressure. An oil isachieved which is polluted by decomposition products of the educt2,5-dichlorotetrahydrofurane, which can be separated by chromatographyon SiO₂.

[0189] (Compare K. Baczko, W -Q. Liu, B. P. Roques, C.Garbay-Jauregiuiberry, Tetrahedron 1996, 52, 2021-30)

[0190] 5-chlorotetrahydrofuryl-2-phosphonic Acid 3(c)

[0191] 0.9 mmol tert-butylester 3(b), 10 ml trifluoroacetic acid, 4.5mmol anisole and 10 ml methylenechloride are stirred at room temperaturefor 1 h. Then 10 ml water are added dropwise thereto and it isconcentrated until dryness. The resulting oil can be recrystallized frommethanol and chloroforme.

[0192] (Compare T. R. Burke Jr., Z -H. Li, J. B. Bolen, V. E. Marquez, JMed Chem 1991, 34, 1577-81)

[0193] The hydrolysis of tert-butylester 3(b) may also be achieved byheating under reflux in benzene by adding trifluoroacetic acid (compareChem. Ber. 1975, 108, 1732-44) or furthermore in pure trifluoroaceticacid at room temperature (compare Phosphorus, sulfur and silicium andrelated elements 1991, 61, 183-84).

[0194] Formohydroxamic Acid 3(d)

[0195] is prepared according to a method of Bernhard et al. J. Am. ChemSoc. 1964, 86, 4406 from hydroxyamine hydrochloride, potassiumchlorideand potassiumhydroxyde, which all are used without further purification.Formohydroxamic acid: melting point: 74-77° C.

[0196] O-trimethylsilylformohydroxamic Acid 3(e)

[0197] 1 equivalent of formohydroxamic acid dissolved in THF is stirredunder addition of triethylamine with 1 equivalent trimethylchlorsilaneat room temperature for 2 days. O-trimethylsilylformohydroxamic acid isachieved in small yields and can be purified by column chromatography.

[0198] 5-(N-formyl-N-hydroxyamino)-tetrahydrofuryl-2-phosphonic Acid3(f)

[0199] 5-chlorotetrahydrofuryl-2-phosphonic acid is stirred with a2-times-surplus of O-trimethylsilylformohydroxamic acid in absolutedimethylformamide at room temperature for 4 h. After quenching withwater it is concentrated under reduced pressure, taken up in water,again concentrated, and the oil is chromatographed on cellulose.

EXAMPLE 4

[0200] 2,6-dichlorotetrahydropyrane 4(a)

[0201] 1 kg 25% watery solution of glutaraldehyde is extracted withmethylenechloride, the organic phase is dried over Na₂SO₄, concentratedand glutaraldehyde is removed by distillation in vacuum (boilingpoint_(13 Torr)=74-75° C.)

[0202] Dry hydrochloric acid is introduced into a solution of 200 gglutaraldehyde dissolved in 700 ml absolute methylenechloride at −25° C.under vigorous stirring, whereby the temperature is kept under −15° C.It allowed to stand at −40° C. for 8 h, subsequently heated to 0° C. andseparated from water. The organic phase is dried over Na₂SO₄, volatileconstituents are removed under reduced pressure and finally2,6-dichlortetrapyrane (a) is distilled (boiling point_(0.01)=37-39°C.).

[0203] (Compare K. Dimroth, W. Kinzebach, M. Soyka, Chem. Ber. 1966, 99,2351-60)

[0204] 6-(N-formyl-N-hydroxyamino)-tetrahydropyryl-2-phosphonic Acid 4(f)

[0205] Pyranderivative 4 can be produced from2,6-dichlorotetrahydropyran as described under 3.

EXAMPLE 5

[0206] 5-(oxo-pyrrolidine-2-yl)-phosphonic Acid Diethylester 5 (a)

[0207] 5-oxo-pyrrolidine derivative 5 (a) can be obtained acording to aninstruction of J. Oleksyszyn, E. Gruszecka, P. Kafafarski, P. Mastalerz,Monatsh. Chem. 1982, 113, 59-72 by the following synthesis sequence:Triethylphosphite and 3-chiorocarbonyl-propionic acid methylester areconverted to 4-(diethoxy-phosphoryl)-4-oxo-butyric acidmethylester. Thisis converted at the 4-oxo position to amine via the oxime.4-amino-4-(diethoxyphosphoryl)butyric acid methylester is cyclized tothe educt compound 5-(oxo-pyrrolidin-2-yl)-phosphonic acid diethylester5 (a) by heating for 30 minutes.

[0208] 5-Thionopyrrolidine-2-phosphonic Acid Diethylester 5(b)

[0209] 10 mmol of the oxo compound 5(a) are converted into the thiocompound 5(b) by P₄S₁₀ in xylol under heating. After the reaction hasbeen completed the yet hot xylol layer is decanted and the product ischromatographed on silica gelic acid.

[0210] 5-Pyrrolidone oxime-2-phosphonic Acid Diethylester 5(c)

[0211] Hydroxyamine is set free from 4.5 g hydroxyamine hydrochloridesuspended in 20 ml methanol by addition of 5.5 g NaHCO₃. 5 g5-thionepyrrolidine 5(b) dissolved in methanol are added thereto. Thesolution is heated until the formation of H₂S is completed (app. 12 h).Then methanol is distilled and the residue is further converted withoutfurther purification.

[0212] (Compare H. Behringer, H. Meier, Liebigs Ann. Chem 1957, 607,67-91)

[0213] 5-(N-hydroxyamino)-pyrrolidine-2-phosphonic Acid Diethylester5(d)

[0214] The reduction of oxime 5(c) to hydroxyamine 5(d) is achievedaccording to the preparation of 1(c). The raw product shows a redcolour, which can be removed by filtration upon active carbon withmethanol as a solvent.

[0215] 5-(N-hydroxyamino)-pyrrolidine-2-phosphonic Acid 5(e)

[0216] Phosphonic acid diethylester 5(d) may be hydrolized in amounts upto 2 g of phosphodiesterase, which is coated on carboxymethylcellulose.

[0217] (Compare I. A. Natchev, Liebigs Ann Chem 1988, 861-867 and I. A.Natchev, Tetrahedron 1988, 44, 1511-22)

[0218] 5-(N-formyl-N-hydroxyamino)-pyrrolidine-2-phosphonic Acid 5(f)

[0219] The regiospecific formylation to N-formyl-N-hydroxylamine 5(e) atthe nitrogen atom of hydroxyamine also results in a bis-formylation. Asreagents for formylation 1,3,5-triformyl-hexahydro-1,3,5-triazine(produced from 1,3,5,7-tetraaza adamantane and formic acid; compare E.N. Gate, M. D. Threadgill, M. F. G. Stevens, D. Chubb, L. M. Vickers, JMed Chem 1986, 29, 1046-52), N-formylimidazole but also formicacid/acetic anhydride are used. 5(e) could not be isolated purely insubstance by chromatography up to now.

EXAMPLE 6

[0220] Piperidin-2-on-6-Phosphonsäurediethylester [6](a) 6. When5-amino-5-(diethoxyphosphoryl)pentanic acid is heated it cyclizes to6(a).

[0221] Further steps also are in analogy to preparation of5-(N-formyl-N-hydroxyamino)-pyrrolidine-2-phosphonic acid 5(e). Also6-(N-formyl-N-hydroxyamino)-piperidine-2-phosphonic acid 6 has also notbeen obtained in substance up to now.

EXAMPLE 7a

[0222] Preparation of compounds HC(═O)—N(OH)—X—PO(OR)₂ with R═H or Na⁺and X═—CH₂—CH₂—C (═O)—

[0223] 3-Chlorpropionyl-phosphonic acid-dimethylester One equivalent oftrimethylphosphite is added dropwise to 0.5 mol 3-chloropropionic acidchloride at 5° C., then heated to ambient temperature and stirred forfurther 2 h. The product is formed in good yields and may be distilledin an oil pump vacuum.

[0224] (by analogy to ref.: R. Karaman, A. Goldblum, E. Breuer, J. ChemSoc Perkin Trans I, 1989, 765-774; preparation of β-chloropropionic acidchloride compare: T. Bruylants, Bull. Soc. Chim. Belg. 1949, 58, 319)

[0225] 3-(N-hydroxyamino)-propionylphosphonic Acid Dimethylester

[0226] Firstly 0,8 mol sodiumhydroxyd, dissolved in 75 ml water, then 75ml methanol and subsequently 0,1 mol 3-chloro propionyl phosphonic aciddimethylester are added dropwise to a solution of 0,8 molhydroxyaminohydrochloride in 100 ml water with cooling with ice. After 3hours of stirring at a temperature of 40° C. methanol is removed underreduced pressure, the resulting watery solution is saturated withNaHCO₃, by—products are removed by washing with toluol and the productis shaken with methylenechloride, dried over magnesiumsulfate, filteredand removed under reduced pressure at room temperature.3-(N-hydroxyamino)propionylphosphonic acid dimethylester remains.

[0227] 3-(N-hydroxyamino)-propionylphosphonic Acid

[0228] 0,2 mol trimethylsilylbromide are slowly added to a solution of0,1 mol 3-(N-hydroxyamino)-propionylphosphonic acid dimethylester in 100ml of absolute acetonitrile. After 3 hours of stirring at roomtemperature the solution is concentrated and taken up in 50 ml methanol.After stirring for 30 minutes it is concentrated again.3-(N-hydroxyamino)-propionylphosphonic acid may be further be convertedwithout purification.

[0229] (by analogy to ref.: R. Karaman, A. Goldblum, E. Breuer, J. Chem.Soc. Perkin. Trans. 1,1989, 765-774)

[0230] 3-(N-formyl-N-hydroxyamino)-propionylphosphonic Acid Mono SodiumSalt

[0231] 2 ml formic acid are added dropwise to 4 ml acetic anhydride at0° C., stirred for 10 min at the same temperature and 15 min at roomtemperature, again cooled to OC and 0,02 mol3-(N-hydroxyamino)propionylphosphonic acid, dissolved in formic acid areadded dropwise at 0° C. After 1 hour of stirring at room temperature thesolution is concentrated under reduced pressure, the oil is dissolved in50 ml methanol, heated to 60° C. and a mixture of ethanol/isopropanol isadded. Ein white solid precipitates, which may be dissolved in methanolonce again and recrystallised from ethanol upon further addition ofisopropanol.

[0232] Alternatively the following way of synthesis may be followed: Theacid chloride of β-alanine is transformed with triethylphosphite into3-aminopropionylphosphonic acid diethylester (compare B. A. Arbuzov, M.V. Zolotova, Bull. Acad. Sci. USSR Div. Chem. Sci (Engl. Transl.) 1964,1701-04). Subsequently it is formylated for oxidizing the resultingsecondary amine to N-formyl-N-hydroxyaminophosphonic acid ester bydimethyldioxirane. The hydrolysis may be carried out as described above.

EXAMPLE 7b

[0233] Preparation of compounds HC (═O)—N(OH)—X—PO(OR)₂ with R═H or Na⁺and X═—CH₂—CH(OH)—C(—O)—

[0234] Instead of 3-chloropropionyichloride acrylic acid is proceededfrom, transformed into the acid chloride, epoxidized by a peracid andthe epoxide is opened radically to obtain3-chloro-2-hydroxypropionylchloride. This may be transformed as inExample 7a.

EXAMPLE 7c:

[0235] Preparation of compounds HC(═O)—N(OH)—X—PO(OR)₂ with R═H or Na⁺and X═—CH₂—CH₂—O—CH₂—

[0236] (2-chloroethoxy)methyl-phosphonic Acid-diethylester

[0237] 1-chloro-2-chloromethoxyethane (Preparation compare: B. Castro,Bull. Soc. Chim. Fr. 1967, 1533-40) is converted with triethylphosphiteunder reflux in a Michael Arbuzov reaction zum(2-Chlor-ethoxy)methylphosphonic acid diethylester.

[0238] (2-Azido-ethoxy)methyl-phosphonic Acid-diethylester

[0239] 0,02 mol (2-chloroethoxy)methyl-phosphonic acid diethylester, 3mmol tetrabutylammoniumbromide and 2,5 g sodiumazide are boiled in 50 mltoluol under reflux for 4 h. After cooling-off it is washed for threetimes with 25 ml water respectively. The watery phase may be extractedwith toluol. The combined toluol phases are dried over sodiumsulfate andthe solvent is removed in the vacuum. A yellow oil remains.

[0240] (compare ref.: K. Eger, E. M. Klunder, M. Schmidt, J. Med. Chem.1994, 37, 3057-61; also compare: A. Holy, I. Rosenberg, Collect. Czech.Chem. Commun. 1989, 2190-210)

[0241] (2-Aminoethoxy)methyl-phosphonic Acid Diethylester

[0242] The above obtained oil (24 mmol) dissolved in 5 ml toluol isadded dropwise to a solution of 36 mmol triphenylphosphine in 35 mltoluol within 30 min. After one hour of stirring at room temperature 50ml of water are added, vigously stirred for 15 min and the phases areseparated. The watery phase is washed with ether for several times andconcentrated. Traces of water are by the help of methanol. A yellow oilremains.

[0243] (compare Lit.: K. Eger, E. M. Klünder, M. Schmidt, J. Med. Chem.1994, 37, 3057-61)

[0244] [2-(N-hydroxyamino)-ethoxy]methyl-phosphonic Acid Diethylester

[0245] (2-aminoethoxy)methylphosphonic acid diethylester can betransformed to the corresponding hydroxyamine in little yields by thecorresponding oxidationsmitteln known in literature (e.g.dimethyldioxirane or benzoylperoxide).

[0246] [2-(N-hydroxyamino)-ethoxy]methyl-phosphonic Acid

[0247] With reference to K -L. Yu, J. J. Bronson, H. Yang, A. Patick, M.Alam, V. Brankovan, R. Datema, M. J. M. Hitchcock, J. C. Martin, J. Med.Chem. 1992, 35, 2958-2969 0.5 mol[2-(N-hydroxyamino)-ethoxy]methylphosphonic acid diethylester and 1 mol2,4,6-collidine in 5 ml of absolute methylenechloride are stirred underargon for one hour at a temperature of 0° C. After allowing to stand for16 hours at room temperature the solution is concentrated in vacuum,taken up in watery acetone and stirred for 14 hours. Subsequently it istaken up in in NaOH and heated to 100° C. for 2 h. After cooling-off itis concentrated and the raw product purified by chromatography.

[0248] [2-(N-Formyl-N-hydroxyamino)-ethoxy]methyl-phosphonic AcidMono-sodium Salt

[0249] Formylation may be carried out by analogy to the description ofExample 7a.

EXAMPLE 7d

[0250] Preparation of compounds HC(═O)—N(OH)—X—PO(OR)₂ with R═H or Na⁺and X═—CH(OH)—CH(OH)—CH(OH)—C(═O)—

[0251] Starting point for X may be threonic acid, threose/erythrose or2.3.4.4-tetrachlorobutyrylchloride (Cl₂C—CHCl—CHCl—COCl) known inliterature.

1. Phosphorous organic compounds of general formula (I)

in which R₁ and R₂ are the same or different and are selected from thegroup, which consists of hydrogen, substituted and unsubstituted alkyl,substituted and unsubstituted hydroxyalkyl, substituted andunsubstituted alkenyl, substituted and unsubstituted alkinyl,substituted and unsubstituted aryl, substituted and unsubstituted acyl,substituted and unsubstituted cycloalkyl, substituted and unsubstitutedaralkyl, substituted and unsubstituted heterocyclic radicals, halogen,OX₁ and OX₂, wherein X₁ and X₂ may be the same or different and areselected from the group, which consists of hydrogen, substituted andunsubstituted alkyl, substituted and unsubstituted hydroxyalkyl,substituted and unsubstituted alkenyl, substituted and unsubstitutedalkinyl, substituted and unsubstituted aryl, substituted andunsubstituted acyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted aralkyl, substituted and unsubstitutedheterocyclic radicals, B is selected from the group, which consists ofether group (II)

wherein A₁ and A₂, of which A₂ also may be absent, are the same ordifferent and are selected from the group, which consists of alkyleneradicals, alkenylene radicals and hydroxyalkylene radicals, keto group(III)

wherein A₃ and A₄, out of which one or both may be absent, are the sameor different and are selected from the group, which consists of alkyleneradicals, alkenylene radicals and hydroxyalkylene radicals, and 5 and 6membered cyclic, especially heterocyclic compounds, which containadditionally to carbon at least one heteroatom as a ring member, whereinthe heteroatom is selected from the group, which consists of oxygen andnitrogen, R₃ and R₄ are the same or different and are selected from thegroup, which consists of hydrogen, substituted and unsubstituted alkylhaving up to 26 carbon atoms, substituted and unsubstituted hydroxyalkylhaving up to 26 carbon atoms, substituted and unsubstituted aryl,substituted and unsubstituted acyl, substituted and unsubstitutedaralkyl, substituted and unsubstituted alkenyl having up to 26 carbonatoms, substituted and unsubstituted alkinyl having up to 26 carbonatoms, substituted and unsubstituted cycloalkyl, substituted andunsubstituted heterocyclic radicals, halogen, OX₃ or OX₄, wherein X₃ orX₄ may be the same or different and are selected from the group, whichconsists of hydrogen, substituted and unsubstituted alkyl having up to26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to26 carbon atoms, substituted and unsubstituted aryl, substituted andunsubstituted aralkyl, substituted and unsubstituted alkenyl having upto 26 carbon atoms, substituted and unsubstituted alkinyl having up to26 carbon atoms, substituted and unsubstituted cycloalkyl, substitutedand unsubstituted heterocyclic radicals, silyl, a cation of an organicand inorganic base, in particular a metal of the first, second, or thirdmain group of the periodic system, ammonium, substituted ammonium andammonium compounds, which derive from ethylene diamine or amino acids,and their pharmaceutically acceptable salts, esters and amides and saltsof the esters.
 2. The compounds according to claim 1, characterized inthat they correspond to formula (IV)

R₂ is selected from the group, which consists of acetyl and formyl, A₁is selected from the group, which consists of methylene, ethylene,ethenylene, 2-hydroxypropylene and hydroxyethylene, R₃ is selected fromthe group, which consists of hydrogen, methyl, ethyl, hexadecyl,octadecyl and OX₃, and X₃ and X₄ are selected from the group, whichconsists of hydrogen, sodium, potassium, methyl, ethyl, hexadecyl andoctadecyl and, as far as both are present, may be the same or different.3. The compounds according to claim 2, characterized in that they areselected from the group, which consists of2-(N-formyl-N-hydroxyamino)-1-oxoethylphosphonic acid disodium salt,2-(N-acetyl-N-hydroxyamino)-1-oxoethylphosphonic acid disodium salt,3-(N-formyl-N-hydroxyamino)-1-oxo propylphosphonic acid disodium salt,3-(N-acetyl-N-hydroxyamino)-1-oxoproylphosphonic acid disodium salt,3-(N-formyl-N-hydroxyamino)-1-oxo-2-propenyl-phosphonic acid disodiumsalt, 3-(N-acetyl-N-hydroxyamino)-1-oxo-2-propenyl phosphonic aciddisodium salt, 4-(N-formyl-N-hydroxyamino)-1-oxo-3-hydroxybutylphosphonic acid disodium salt,4-(N-acetyl-N-hydroxyamino)-1-oxo-3-hydroxybutylphosphonic acid disodiumsalt, 3-(N-formyl-N-hydroxyamino)-2-oxopropyl phosphonic acid disodiumsalt, 3-(N-acetyl-N-hydroxyamino)-2-oxoproylphosphonic acid disodiumsalt,4-(N-formyl-N-hydroxyamino)-3-oxo-2-hydroxy-2-methylbutylphosphonic aciddisodium salt,4-(N-acetyl-N-hydroxyamino)-3-oxo-2-hydroxy-2-methylpropylphosphonicacid disodium salt,4-(N-formyl-N-hydroxyamino)-3-oxo-2-hydroxy-2-(hydroxymethyl)butylphosphonicacid disodium salt,4-(N-acetyl-N-hydroxyamino)-3-oxo-2-hydroxy-2-(hydroxymethyl)propylphosphonicacid disodium salt.
 4. The compounds according to claim 1, characterizedin that they correspond to the formula (V)

R₂ is selected from the group, which consists of acetyl and formyl, A₃is selected from the group, which consists of methylene, ethylene,ethenylene, 2-hydroxypropylene, hydroxymethylen and hydroxyethylene, A₄is absent or is methylene, and R₃ is selected from the group, whichconsists of hydrogen, methyl, ethyl, hexadecyl, octadecyl and OX₃, andX₃ and X₄ are selected from the group, which consists of hydrogen,sodium, potassium, methyl, ethyl, hexadecyl and octadecyl and, as far asboth are present, may be the same or different.
 5. The compoundsaccording to claim 4, characterized in that they are selected from thegroup, which consists of((N-formyl-N-hydroxyamino)-methoxy)-methylphosphonic acid disodium salt,((N-acetyl-N-hydroxyamino)-methoxy)-methyl phosphonic acid disodiumsalt, (2-(N-formyl-N-hydroxy amino)-ethenoxy)-methylphosphonic aciddisodium salt, (2-(N-acetyl-N-hydroxyamino)-ethenoxy)-methylphosphonicacid disodium salt, (3-(N-formyl-N-hydroxyamino)-2-hydroxypropoxy)-methylphosphonic acid disodium salt,(3-(N-acetyl-N-hydroxyamino)-2-hydroxypropoxy)-methylphosphonic aciddisodium salt.
 6. The compounds according to claim 1, characterized inthat B is a cyclic compound, wherein the amino group and the phosphorusatom are bound to two C atoms which are separated only by one furtheratom.
 7. The compounds according to claim 6, characterized in that B isa heterocyclic compound, wherein the amino group and the phosphorus atomare bound to two C-atoms which are only separated by one heteroatom. 8.The compounds according to claim 7, characterized in that thephosphororganic compound is selected from the group, which consists ofcompounds of the formulae

wherein X₁ represents H, R₂ is selected from the group, which consistsof acetyl and formyl, and X₃ and X₄ are the same or different and areselected from the group, which consists of hydrogen, sodium, potassium,methyl, ethyl, hexadecyl and octadecyl.
 9. Pharmaceutical preparation,characterized by a effective content of at least one phosphorous organiccompound according to one of claims 1 to 8 together with apharmaceutically acceptable excipient.
 10. Pharmaceutical preparationaccording to claim 9, characterized by at least one furtherpharmaceutical active ingredient.
 11. Pharmaceutical preparationaccording to one of the claims 9 or 10, characterized by one or moreingredients out of the group which consists of sulfonamide, sulfadoxin,artemisinin, atovaquon, chinin, chloroquine, hydroxychloroquin,mefloquin, halofantrin, pyrimethamine, armesin, tetracycline,doxycyclin, proguanil, metronidazol, praziquantil, niclosamide,mebendazol, pyrantel, tiabendazole, diethylcarbazin, piperazin,pyrivinum, metrifonate, oxamniquin, bithionol and suramin. 12.Pharmaceutical preparation according to claim 10, characterized by oneor more ingredients of the group which consists of penicillins, benzylpenicillin (Penicillin G), phenoxy penicilline, isoxazolyl penicillins,amino penicillins, ampicillin, amoxicillin, bacampicillin, carboxypenicillin, ticarcillin, temocillin, acyalamino penicillins, azlocillin,mezlocillin, piperacillin, apalcillin, mecillinam, cephalosporins,cefazolin group, cefuroxime group, cefoxitin group, cefoxitin,cefotetan, cefinetazole, latamoxef, flomoxef, cefotaxime group,cefozidime, ceftazidime group, ceftazidime, cefpirom, cefepim, remainingcephalosporins, cefsulodine, cefoperazone, oralcephalosporins of thecefalexin group, loracarbef, cefprozil, new oralcephalosporins withexpanded spectrum, cefixime, cefpodoxime proxetil, cefuroxime axetil,cefetamet, cefotiam hexetil, cefdinir, ceftibutene, other B-lactamantibiotics, carbapenem, imipenem/cilastatin, meropenem, biapenem,aztreonam, B-lactamase inhibitors, calvulanic acid/amoxicillin,Clavulanic acid/ticarcillin, sulbactam/ampicillin,tazobactam/piperacillin, tetracyclines, oxytetracycline,rolitetracyclines, doxycycline, minocycline, chloramphenicol,aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin,spectinomycin, macrolides, erythromycin, clarithromycin, roxithromycin,azithromycin, dirithromycin, spiramycin, josamycin, lincosamides,clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin,tecoplanin, pristinamycin derivatives, fosfomycin, antimicrobial folicacid antagonists, sulphonamides, co-trimoxazole, trimethoprim, otherdiaminopyrimidine sulfonamide combinations, nitrofurans, nitrofurantoin,nitrofurazone, Gyrase inhibitors (quinolones), norfloxacin,ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin,pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles, antimycobacterialagents, isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide,streptomycin, capreomycin, prothionamide, terizidon, dapsone,clofazimine, topical antibiotics, bacitracin, tyrothricin, polymyxins,neomycin, kanamycin, paromomycin, mupirocin, antiviral agents,acyclovir, ganciclovir, azidothymidine, didanosin zalcitabin,thiacytidine, stavudin, ribavirin, idoxuridine, trifluridine, foscarnet,amantadine, interferons, tibol derivatives, proteinase inhibitors,antifungal agents, polyenes, amphothericin B, nystatin, natamycin,azoles, azoles for septic treatment, miconazole, ketoconazole,itraconazole, fluconazole, UK-109.496, azoles for topical application,clotrimazole, econazole, isoconazole, oxiconazole, bifonazole,flucytosine, griseofulvin, ciclopiroxolamine, tolnaftate, naftifine,terbinafine, amorolfine, antraquinones, betulinic acid,semianthrachinones, xanthones, naphtoquinones, aryaminoalcohols,quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine,acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone,sulphonamides, sulfadoxine, sulfalenes, trimethoprim, proguanil,chlorproguanil, diaminopyrimidines, pyrimethamine, primaquine,aminoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin,norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin,10b arte mether, arte ether, arte sunate, atovaquon, suramin,melarsoprol, nifurtimox, stibogluconate-sodium, pentamidine,amphotericine B, metronidazole, clioquinole, mebendazole, niclosamide,praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin,bithionol, oxamniquine, metrifonate, piperazine, embonate.
 13. Use ofphosphorous organic compounds according to one of claims 1 to 8 forpreparing pharmaceutical compositions for the treatment of infectiousprocesses in humans and animals due to viruses, bacteria, fungi orparasites and as fungicides, bactericides or herbicides in plant. 14.Use according to claim 13 for the preparation of pharmaceuticalcompositions for the treatment of infections due to bacteria, viruses,fungi or unicellular or multicellular parasites.
 15. Use according toclaim 13 for the preparation of pharmaceutical compositions for thetreatment of infections caused by bacteria which are selected from thegroup, which consists of Bacteria of the family Propionibacteriaceae, inparticular the genus Propionibacterium, in particular the speciesPropionibacterium acnes; bacteria of the family Actinomycetaceae, inparticular the genus Actinomyces; bacteria of the genus Corynebacterium,in particular the species Corynebacterium diphteriae and Corynebacteriumpseudotuberculosis; bacteria of the family Mycobacteriaceae, the genusMycobacterium, in particular the species Mycobacterium leprae,Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium;bacteria of the family Chlamydiaceae, in particular the speciesChlamydia trachomatis and Chlamydia psittaci; bacteria of the genusListeria, in particular the species Listeria monocytogenes; bacteria ofthe species Erysipelthrix rhusiopathiae; bacteria of the genusClostridium; bacteria of the genus Yersinia, the species Yersiniapestis, Yersinia pseudotuberculosis, Yersinia enterocolitica andYersinia ruckeri; bacteria of the family Mycoplasmataceae, the genusMycoplasma and Ureaplasma, in particular the species Mycoplasmapneumoniae; bacteria of the genus Brucella; bacteria of the genusBordetella; bacteria of the family Neiseriaceae, in particular thegenuses Neisseria and Moraxella, in particular the species Neisseriameningitides, Neisseria gonorrhoeae and Moraxella bovis; bacteria of thefamily Vibrionaceae, in particular the genuses Vibrio, Aeromonas,Plesiomonas and Photobacterium, in particular the species Vibriocholerae, Vibrio anguillarum and Aeromonas salmonicidas; bacteria of thegenus Campylobacter, in particular the species Campylobacter jejuni,Campylobacter coli and Campylobacter fetus; bacteria of the genusHelicobacter, in particular the species Helicobacter pylori; bacteria ofthe families Spirochaetaceae and the Leptospiraceae, in particular thegenus Treponema, Borrelia and Leptospira, in particular Borreliaburgdorferi; bacteria of the genus Actinobacillus; bacteria of thefamily Legionellaceae, the genus Legionella; bacteria of the familyRickettsiaceae and family Bartonellaceae; bacteria of the genus Nocardiaand Rhodococcus; bacteria of the genus Dermatophilus; bacteria of thefamily Pseudomonadaceae, in particular the genuses Pseudomonas andXanthomonas; bacteria of the family Enterobacteriaceae, in particularthe genuses Escherichia, Klebsiella, Proteus, Providencia, Salmonella,Serratia and Shigella; bacteria of the family Pasteurellaceae, inparticular the genus Haemophilus; bacteria of the family Micrococcaceae,in particular the genus Micrococcus and Staphylococcus; bacteria of thefamily Streptococcaceae, in particular the genus Streptococcus andEnterococcus and bacteria of the family Bacillaceae, in particular thegenus bacillus and clostridium, and in the helicobacter eradicationtherapy of ulcera of the gastro-intestinal tract.
 16. Use according toclaim 13 for the preparation of pharmaceutical compositions for thetreatment of infections caused by viruses which are selected from thegroup, which consists of viruses of the parvoviridae, in particularparvo viruses, dependo viruses, denso viruses, viruses of the genusadenoviridae, in particular adeno viruses, mastadeno viruses, aviadenoviruses, viruses of the genus papovaviridae, in particular papovaviruses, in particular papilloma viruses (so called wart viruses),polyoma viruses, in particular JC-virus, BK-virus, and miopapovaviruses, viruses of the genus herpes viridae, in particular herpessimplex viruses, the varizella-zoster viruses, human cytomegalo virus,Epstein-Barr viruses, human herpes virus 6, human herpes virus 7, humanherpes virus 8, viruses of the genus poxyiridae, in particular poxviruses, orthopox, parapox, molluscum contagiosum virus, avipox viruses,capripox viruses, leporipox viruses, primary hepatotropic viruses, inparticular hepatitis viruses, such as hepatitis A viruses, hepatitis Bviruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses,hepatitis F viruses, hepatitis G viruses, hepadna viruses, in particularall hepatitis viruses, such as hepatitis B virus, hepatitis D viruses,viruses of the genus picornaviridae, in particular picorna viruses, allentero viruses, all polio viruses, all coxsackie viruses, all echoviruses, all rhino viruses, hepatitis A virus, aphtho viruses, virusesof the genus Calciviridae, in particular hepatitis E viruses, viruses ofthe genus Reoviridae, in particular reo viruses, orbi viruses, rotaviruses, viruses of the genus togaviridae, in particular toga viruses,alpha viruses, rubi viruses, pesti viruses, rubella virus, viruses ofthe genus flaviviridae, in particular flavi viruses, FSME virus,hepatitis C virus, viruses of the genus orthomyxoviridae, in particularinfluenza viruses, viruses of the genus Paramyxoviridae, in particularparamyxo viruses, morbilli virus, pneumo virus, measles virus, mumpsvirus, viruses of the genus rhabdoviridae, in particular rhabdo viruses,rabies virus, lyssa virus, viscula stomatitis virus, viruses of thegenus corona viridae, in particular corona viruses, viruses of the genusbunyaviridae, in particular bunya viruses, nairo virus, phlebo virus,uuku virus, hanta virus, viruses of the genus arenaviridae, inparticular arenaviruses, lymphocytic choriomeningitis virus, viruses ofthe genus retroviridae, in particular retro viruses, all HTL viruses,human T-cell leukaemia virus, oncorna viruses, spuma viruses, lentiviruses, all HI-viruses, viruses of the genus filoviridae, in particularMarburg and Ebola virus, Slow viruses, prions, onko viruses and leukemiaviruses.
 17. Use according to claim 13 for the preparation ofpharmaceutical compositions for prophylactics and treatment ofinfections caused by unicellular parasites, namely pathogens of malaria,the sleeping sickness, the Chagas' disease, the toxoplasmosis, amoebicdysentery, leishmaniasis, trichomoniasis, pnemacystosis, balantidiosis,cryptosporidiosis, sarcocystosis, acanthamebiasis, naegleriasis,coccidiosis, giardiasis and lambliosis.